Early Estimates of Updated 2023–2024 (Monovalent XBB.1.5) COVID-19 Vaccine Effectiveness Against Symptomatic SARS-CoV-2 Infection Attributable to Co-Circulating Omicron Variants Among Immunocompetent Adults — Increasing Community Access to Testing Program, United States, September 2023–January 2024

On September 12, 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (updated) COVID-19 vaccination with a monovalent XBB.1.5-derived vaccine for all persons aged ≥6 months to prevent COVID-19, including severe disease. During fall 2023, XBB lineages co-circulated with JN.1, an Omicron BA.2.86 lineage that emerged in September 2023. These variants have amino acid substitutions that might increase escape from neutralizing antibodies. XBB lineages predominated through December 2023, when JN.1 became predominant in the United States. Reduction or failure of spike gene (S-gene) amplification (i.e., S-gene target failure [SGTF]) in real-time reverse transcription-polymerase chain reaction testing is a time-dependent, proxy indicator of JN.1 infection. Data from the Increasing Community Access to Testing SARS-CoV-2 pharmacy testing program were analyzed to estimate updated COVID-19 vaccine effectiveness (VE) (i.e., receipt versus no receipt of updated vaccination) against symptomatic SARS-CoV-2 infection, including by SGTF result. Among 9,222 total eligible tests, overall VE among adults aged ≥18 years was 54% (95% CI = 46%-60%) at a median of 52 days after vaccination. Among 2,199 tests performed at a laboratory with SGTF testing, VE 60-119 days after vaccination was 49% (95% CI = 19%-68%) among tests exhibiting SGTF and 60% (95% CI = 35%-75%) among tests without SGTF. Updated COVID-19 vaccines provide protection against symptomatic infection, including against currently circulating lineages. CDC will continue monitoring VE, including for expected waning and against severe disease. All persons aged ≥6 months should receive an updated COVID-19 vaccine dose.


Introduction
On September 12, 2023, CDC's Advisory Committee on Immunization Practices recommended that all persons aged ≥6 months receive the updated 2023-2024 (updated) monovalent COVID-19 vaccine (1).Most persons aged ≥5 years are recommended to receive 1 updated dose.These vaccines contain a component from the SARS-CoV-2 Omicron XBB.1.5lineage and unlike previous COVID-19 vaccines, do not contain the ancestral SARS-CoV-2 strain.During the period of analysis, XBB lineages predominated early, many with evolutionarily advantageous amino acid changes in the spike gene (S-gene).In September 2023, the divergent JN.1 lineage was detected in the United States.JN.1 has more than 30 mutations in the spike protein compared with XBB.1.5,including a change (L455S) similar to one found in circulating XBB lineages (L455F).*JN.1 accounted for 69% (range = 65%-73%) of SARS-CoV-2 infections nationally by the 2-week period ending January 6, 2024.† Results of spike gene (S-gene) amplification in real-time reverse transcription-polymerase chain reaction (RT-PCR) can be used to distinguish certain SARS-CoV-2 lineages over time (2).Detection of S-gene target presence (SGTP) by a widely used commercial test was noted in most lineages that circulated in 2023, including XBB lineages, § whereas S-gene target failure (SGTF), resulting from a mutation in the S-gene, is detected in JN.1 and other BA.2.86 lineages.¶   For the SGTF and SGTP subanalysis, overall VE (regardless of time since dose) and VE during the 7-59 days after an updated dose were not calculated because the emergence of JN.1 parallels time since dose; statistical power for SGTF (likely JN.1) during the 7-59 days was therefore limited.Analyses were conducted using R software (version 4.1.2;R Foundation).This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.† † † †

Secondary VE Analyses
Secondary analyses showed similar VE estimates for receipt of updated vaccine compared with those who previously received only original monovalent doses and those who received original monovalent and bivalent doses.(Supplementary Table ; https:// stacks.cdc.gov/view/cdc/145937).

Discussion
This report provides early estimates of effectiveness of updated monovalent XBB.1.5COVID-19 vaccines against symptomatic SARS-CoV-2 infection and the first estimates of VE against symptomatic infection with the JN.1 lineage.These preliminary estimates from pharmacy testing conducted during September 2023-January 2024 showed updated monovalent COVID-19 vaccine provided protection for JN.1 and other circulating lineages.
VE against symptomatic infection provides helpful information about the range of protection provided by updated vaccines and against emerging lineages.An important strength of ICATT SARS-CoV-2 testing data is the ability to distinguish JN.1 from XBB lineages, allowing for comparison of VE during the same period after vaccination.Monitoring the potential impact on VE of JN.1 is critical because of the spike mutations in JN.1 (as compared with XBB lineages), which might be associated with increased immune escape § § § § (5).Recent laboratory data show that the updated vaccines elicit neutralizing antibodies against emerging XBB lineages and JN.1 (6).Although point estimates during the 60-119 days after vaccination were lower for SGTF than SGTP results in this analysis, CIs overlapped, indicating no statistically significant difference.These data provide reassurance that updated vaccines are providing protection against JN.1 and XBB lineages.
These early estimates include the period only through 119 days since vaccination, a relatively brief postvaccination § § § § JN.1 is a sublineage of BA.2.86, defined by the spike substitution L455S.
Changes at this amino acid position have conferred immune escape advantages to other lineages and might be associated with increased immune escape.period, with no substantial waning.Because consistent patterns of waning VE were observed after original monovalent and bivalent COVID-19 vaccination, waning of VE is expected with more time since updated vaccination, especially against less severe outcomes such as symptomatic infection.Additional analyses conducted at longer intervals since authorization of updated vaccines are needed for continued monitoring of expected waning and to determine how well vaccines are working to prevent severe disease.

Limitations
The findings in this report are subject to at least five limitations.First, vaccination status, previous infection history, and underlying medical conditions were self-reported and might be subject to recall bias.Self-reported frequency of previous infections >90 days before testing differed by vaccination status and SGTF status, but statistical power was not adequate for stratification of results.Further, previous infection is likely underreported (7).Previous infection provides some protection against repeat infection (8) and U.S. adults have a high population choosing to be tested for SARS-CoV-2 and are potentially subject to selection biases related to these factors.In addition, updated vaccination coverage to date has been low (approximately 22% as of January 13, 2024*****) among persons aged ≥18 years and varies by age, which could bias results if persons being vaccinated earlier are systematically different from those vaccinated later.Thus, residual confounding might be present and could affect these early estimates.Fourth, this Vaccine effectiveness (VE) of receipt of updated COVID-19 vaccine in preventing symptomatic SARS-CoV-2 infection was assessed in adults aged ≥18 years, by time since dose and by SGTF and SGTP as a proxy for likely JN.1 versus other lineages.Whereas the goal of the U.S. COVID-19 vaccination program is to prevent severe disease, VE against symptomatic infection can provide useful insights into protection early after introduction of updated vaccines and during the emergence of new lineages, such as JN.1.US Department of Health and Human Services | Centers for Disease Control and Prevention | MMWR | February 1, 2024 | Vol.73 | No. 4

Methods Overall Assessment of VE
6) registration for testing with a version of the questionnaire that only reported month and year of the most recent vaccine dose rather than calendar date.In addition, tests from persons reporting receipt of a positive SARS-CoV-2 test result during the preceding 90 days § § § were excluded.Type of most recent vaccine dose (original monovalent, bivalent, or updated monovalent) was determined by the reported date of receipt of the dose.¶ ¶ ¶ VE against symptomatic disease was calculated by comparing odds of receipt versus nonreceipt of the updated COVID-19 vaccine among case-and control patients.Secondary analyses examined alternative reference groups, including 1) receipt of a bivalent dose and 2) being either unvaccinated or having received only original COVID-19 vaccines.Odds ratios (ORs) were estimated using multivariable logistic regression****; VE was calculated separately based on SGTF or SGTP status as (1 − OR) x 100%.

of VE by SGTF and Time Since Vaccination A
(2,4)alysis of VE by SGTF status and time since last dose included RT-PCR tests performed by one pharmacy chain during October 27, 2023-January 12, 2024, and analyzed at a commercial laboratory that used the TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific).Quantitative results were reported as cycle threshold (Ct) values for each of three SARS-CoV-2 gene targets (S, N, and ORF1ab).Only specimens with Ct values available for both N and ORF1ab were § § § Tests from persons reporting a positive SARS-CoV-2 test result during the preceding 90 days were excluded to avoid analyzing multiple tests for the same illness episode or reinfections within a relatively short time frame.intheSGTF subanalysis.SARS-CoV-2-positive specimens with either null or reduced amplification of the S-gene (Ct for S-gene >4 cycles from the average of N and ORF1ab Ct values) were considered to have SGTF(2,4), an indication of a particular deletion in the SARS-CoV-2 spike protein, which currently indicates an infection with BA.2.86, https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/testing.kidney failure or end stage renal disease, cirrhosis of the liver, and chronic lung disease (such as chronic obstructive pulmonary disease, moderate to severe asthma, cystic fibrosis, or pulmonary embolism).included